BLR&D Research Career Scientist Award Application

项目摘要/摘要： 本课题组的主要研究重点是了解胰腺的潜在分子机制。 以及乳腺癌的发病机制。我们研究的首要目标是研究细胞通路是如何 (例如，电路)不受调控，可能导致细胞生长失控(即癌症)。最终目标是 开发和使用小分子来靶向失调的蛋白质，这些蛋白质是胰腺的根本原因 以及乳腺癌的发病机制。 我们的实验室一直在研究一组蛋白质，称为混合血统蛋白激酶(MLK)。的角色 MLK在癌症中的作用是一个新兴领域，该家族的抑制剂已经通过了治疗帕金森氏症的临床试验 疾病。我们已经证明MLKs的抑制剂可以被重新用于治疗三阴性乳腺癌(TNBC)。 和胰腺导管腺癌(PDAC)。 我们最近的结果(通过VA-MERIT资助)表明MLK家族成员之一MLK3高度 在人胰腺癌肿瘤中高表达，是细胞生长所必需的。此外，使用动物 在胰腺癌模型中，我们观察到MLKs抑制剂改善了PDAC和动物的存活 与车辆处理的动物相比，时间要长得多。我们计划进一步探索MLK3失调是如何促进 并最终使用这些抑制剂进行治疗干预。 另外两个项目(由NCI/NIH的两笔赠款资助)是关于乳腺癌的。我们早些时候报道过， 雌激素抑制MLK3活性对于ER+乳腺癌细胞的生存和生长是必要的。我们 还观察到另一种受体HER2也能够抑制HER2+乳腺癌中MLK3的活性 这对他们的生存也是必要的。总而言之，这些令人兴奋的结果表明，抑制 ER和HER2对MLK3的表达为乳腺癌细胞的生长和增殖提供了生存信号。因此， 我们开发了一种新型的纳米颗粒，负载了MLK3激活剂神经酰胺(一种脂类)，能够诱导 HER2+和ER+乳腺癌细胞显著死亡。在ER+和HER2+乳腺癌的动物模型中， 神经酰胺纳米粒能够减轻肿瘤负担。此外，我们还观察到，在人的TNBC中 与ER+乳腺癌相比，MLK3的活性非常高。通过机械学研究， 我们发现MLK3活性在TNBC中扮演着矛盾的生存角色。基于我们的细胞和人类 肿瘤数据，移植了TNBC肿瘤(即PDX)的动物被MLKs抑制剂治疗，实际上 减轻了肿瘤负担，延长了动物寿命。我们的结果最先证明了 MLK3/MLKs抑制剂可显著减轻TNBC肿瘤负担，延长动物生命。同样， 根据我们的细胞和人类肿瘤数据，Herceptin(即抗HER2+治疗)的肿瘤负荷耐药 人在动物体内的肿瘤(即PDX)减少。 综上所述，我们的结果提示MLK3/MLKs激活剂可用于治疗ER+和 HER2+乳腺癌，而MLK3/MLKs抑制剂可作为对TNBC的治疗干预 和胰腺导管腺癌(PDAC)。我们的综合研究也表明， 在使用任何有针对性的药物之前，了解疾病潜在的分子机制是很重要的 心理治疗。

Project Summary/Abstract: The main focus of research in our group is to understand the underlying molecular mechanisms of pancreatic and breast cancer pathogenesis. The overarching goal of our research is to investigate how the cellular pathways (i.e. circuits) are dysregulated and can lead to uncontrolled cell growth (i.e. cancer). The ultimate goal is to develop and use small molecules to target the dysregulated proteins that are the underlying cause of pancreatic and breast cancers pathogenesis. Our laboratory has been working with a group of proteins, called Mixed Lineage Kinases (MLKs). The roles of MLKs in cancer is an emerging area and the inhibitor of this family has gone through clinical trial for Parkinson's Disease. We have shown that inhibitor of MLKs can be repurposed to treat Triple Negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC). Our recent results (funded through VA-Merit) demonstrate that one of the MLK family member, MLK3 was highly overexpressed in human pancreatic cancer tumors and was necessary for cell growth. Furthermore, using animal models of pancreatic cancer, we have observed that MLKs inhibitor ameliorate PDAC and the animals survive much longer, compared to vehicle treated animals. We plan to further explore how MLK3 dysregulation promotes pancreatic cancer and ultimately use the inhibitors for therapeutic intervention. The other two projects (funded through 2 NCI/NIH grants) are on breast cancer. We reported earlier that suppression of MLK3 activity by Estrogen was necessary for ER+ breast cancer cell survival and growth. We also observed that the other receptor, HER2 was also able to suppress MLK3 activity in HER2+ breast cancer and this was also necessary for their survival. Taken together, these exciting results suggest that suppression of MLK3 by ER and HER2 provides survival signals for breast cancer cell growth and proliferation. Therefore, we developed a novel nanoparticle, loaded with MLK3 activator, ceramide (a lipid) that was able to induce significant cell death in HER2+ and ER+ breast cancer cells. In animal models of ER+ and HER2+ breast cancer, the ceramide-nanoparticle was able to reduce tumor burden. In addition, we also observed that in human TNBC tumors, the activity of MLK3 was very high compared to ER+ breast cancer tumors. Through mechanistic studies, we identified that MLK3 activity plays paradoxically a survival role in TNBC. Based on our cellular and human tumor data, the animal transplanted with TNBC tumors (i.e. PDXs) were treated with MLKs inhibitors, indeed the tumor burden was reduced and the animal life was prolonged. Our results are first in line to demonstrate that MLK3/MLKs inhibitors can significantly reduce TNBC tumor burden and can prolog animals' life. Similarly, following our cellular and human tumor data, the tumor burden of Herceptin (i.e. anti-HER2+ therapy) resistant human tumors in animal (i.e. PDXs) was reduced. Taken together, our results suggest conclusively that activator of MLK3/MLKs could be used to treat ER+ and HER2+ breast cancer, whereas the inhibitor of MLK3/MLKs could serve as a therapeutic intervention for TNBC and pancreatic ductal adenocarcinoma (PDAC). Our comprehensive studies also suggest that it is utmost important to understand the detail underlying molecular mechanisms of a disease before using any targeted therapy.